The findings could help researchers better understand how people with depression respond to treatment.
Ketamine can act quickly against depression that has not improved with other treatments. In a study of U.S. veterans over 55, researchers found that the brain’s response continued to change over the following week, with one pattern of activity linked to greater relief from depressive symptoms.
The team at Texas A&M University’s Naresh K. Vashisht College of Medicine found distinct patterns of brain activity one hour, 24 hours, and seven days after a single ketamine infusion. At 24 hours, larger increases in one measure of information sharing across the brain were associated with greater symptom improvement on day seven. The findings were published in Translational Psychiatry.
Older adults remain underrepresented in ketamine research
Ketamine is increasingly used for treatment-resistant depression, but its use in older adults has been limited by questions about safety and effectiveness in people with health conditions associated with aging. At Texas A&M, the Experimental Psychopharmacology of Mood and Anxiety Disorders Lab, or EPMAD Lab, has been investigating those questions in veterans over 55. The lab is led by Dr. Sanjay Mathew, professor and head of Psychiatry.
Two earlier publications from the group found that intravenous ketamine, delivered through a vein, was feasible and effective in older adults. The new research examined how communication across the brain changes after treatment, seeking clues to why patients experience different levels of benefit.
Dr. Nicholas Murphy, a research associate professor in Texas A&M’s Department of Psychiatry and Behavioral Sciences, coordinates the EPMAD Lab’s work on treatments informed by neuroscience. He said older patients have often been left out of the research needed to understand those responses.
“Most drug studies end at age 65, leaving relatively little research on how ketamine affects the aging brain,” Murphy said. “Although older adults make up more than one-third of the nation’s population, they remain underrepresented in clinical research.”
Looking beyond pairs of brain signals
For the new study, the Texas A&M team worked with researchers at Baylor College of Medicine and the University of the Balearic Islands to analyze brain activity over the hours and days following an infusion. They used electroencephalography, or EEG, which records the brain’s electrical activity through sensors on the scalp.
Krisha Shah, a research associate in Texas A&M’s Department of Psychiatry and Behavioral Sciences, explained why the team needed to examine communication across a broader network of brain signals.
“Often, EEG research looks at individual brain signals or communication between pairs of signals, but the brain doesn’t operate in pairs. It’s a highly interconnected system,” she said. “Ketamine is unusual because the drug exposure is brief, but antidepressant effects have the potential to extend well beyond that experience.”
The researchers used an approach called higher-order interactions to examine how information was organized across multiple EEG signals at once. Drawing on information theory, a mathematical framework for studying information and its relationships, the approach allowed them to look beyond individual signals or connections between pairs. The study also replicated and extended earlier research that used higher-order interactions in healthy volunteers.
Brain flexibility may shape ketamine’s effects
Murphy suggests that the brain’s ability to adapt may be more closely tied to a patient’s clinical response than the size of its initial reaction to ketamine. His explanation centers on glutamate, a chemical messenger that nerve cells use to communicate, and how the communication enabled by ketamine becomes organized.
“Let’s say you had a map of rivers in the desert,” he said. “You release the dam, and now all the tributaries are being flooded with water. We now have these connections between places, and that’s what ketamine does; it helps to create a more flexible and densely connected environment. But this isn’t the end of the story. For it to be useful, we need to understand how that water is flowing, and that’s where our current analysis comes in. It tells us how the surging of glutamate released by ketamine needs to flow to get a clinical response.”
The brain-signal changes identified in the study could serve as biomarkers, or measurable biological signs, associated with ketamine’s antidepressant effects in older adults. Identifying when those changes occur could also help researchers investigate other ways to produce therapeutic effects.
“Ketamine has come a long way from its humble beginnings as an anesthetic,” Murphy said. “However, it still has a strong abuse potential. The goal of the work that my team has been doing is to identify these key points in that physiological roadmap so it can be acted upon via another mechanism that doesn’t have the psychedelic or medical side effects of ketamine.”
Reference: “High-order brain interactions during ketamine-induced state changes: A functional marker of response in late-life treatment-resistant depression?” by Krisha Shah, Rubén Herzog, Alan C. Swann, Brittany O’Brien, Rahul Balakrishnan, Sanjay J. Mathew and Nicholas Murphy, 4 July 2026, Translational Psychiatry.
DOI: 10.1038/s41398-026-04212-1
This work is supported by a Department of Veterans Affairs Merit Award (Grant # CX-001205-01AI) awarded to S.J. Mathew, and with the use of facilities and resources of the Michael E DeBakey VA Medical Center, Houston, Texas.
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